Aβ vaccination in conjunction with bee venom derived phospholipase A2 (bvPLA2) ameliorates Alzheimer’s disease pathology through the induction of Aβ-specific Treg population in 3xTg-AD mice

Abstract Alzheimer’s disease (AD) is the most common form of dementia and characterized by an imbalance between the production and clearance of amyloid-beta (Aβ) and tau proteins. Vaccination against Aβ peptide results in dramatic reduction of Aβ pathology in experimental mouse models. Our recent study demonstrated that bvPLA2, the major component of BV, causes immune tolerance by increasing the population of CD4+CD25+Foxp3+ Tregs in cisplatin-induced nephrotoxicity, an allergic asthma and Parkinson disease murine model. Here, we investigated that the effect of bvPLA2 to induce antigen-specific Tregs to ameliorate Alzheimer’s disease (AD) pathology through linked immunosuppression. First, we investigated whether bvPLA2 would improve the cognitive function and the pathological features of AD in Aβ-vaccinated-3xTg-AD mice. bvPLA2 treatment dramatically ameliorated learning and memory deficits in Aβ-vaccinated-AD mice. In addition, bvPLA2 significantly reduced Aβ deposits in the hippocampus and cortex region of AD mice, compared with the Aβ-vaccinated-AD mice group. Next, we systemically administered Aβ-specific Treg populations generated in the absence or presence of bvPLA2 into 3xTg-AD mice. Systemic transplantation of Aβ-specific Tregs into 3xTg-AD mice improved cognitive function and reduced deposition of Aβ plaques. Furthermore, adoptive transfer of Tregs generated in the presence of bvPLA2 showed reduced Aβ plaques and diminished learning and memory ability compared with Tregs generated in the absence of bvPLA2. This opens the possibility of new therapeutic strategy to target Tregs to tissue-specific antigens for the treatment of AD.